The long-term objectives of this prospective cohort study are to (1) characterize the spectrum of nervous system (NS) involvement in patients with systemic lupus erythematosus (SLE), a significant cause of morbidity in up to 75 percent of patients and (2) define important risk factors which may be unique for specifically targeted NS manifestations including stroke, cognitive dysfunction, and psychiatric manifestations. Our preliminary data suggests that the frequency of stroke and other NS manifestations in our predominately Mexican-American (MA) SLE population is high. The specific hypotheses which will be tested in this proposed 5-year project are: (1) the risk of initial thrombo-occlusive events will be higher in SLE patients who have persistently abnormal levels of antiphospholipid (aPL) and antiapolipoprotein H (anti-apoH) antibodies; (2) the development of cognitive dysfunction in SLE patients will be temporally associated with abnormal levels of aPL and anti-apoH antibodies; (3) the development of psychiatric manifestations (psychosis, depression, or anxiety) in SLE patients will be temporally associated with abnormal serum levels of antiribosomal P (anti-P) antibodies for SLE disease activity, cumulative SLE-related organ damage or the presence of cardiovascular risk factors will all contribute to the risk of developing targeted NS manifestations in a way that is independent of aPL, anti-apoH or anti-P antibody status. We will perform serial neurological, cognitive, psychiatric, rheumatological and immunological evaluations every four months and at the time of an endpoint event occurrence over a five year period. Kaplan-Meier curves will be constructed comparing the time between thrombotic events and antibody positive and negative groups. Cox regression will be used to construct multivariate models to control for the effects of the potential confounders. Cognitive dysfunction will be measured as a continuous variable, with fluctuations in functioning about the baseline for each patient compared with antibody levels. Close attention will be paid to problems of multiple comparisons. An approach similar to that described for cognitive dysfunction will be used for psychiatric manifestations. The project will identify risk factors which may account for significant morbidity in and provide crucial natural history data about SLE-related NS manifestations which are currently unavailable. The information gained will bridge important gaps in our knowledge about NS involvement in SLE and will lead to new hypothesis-driven studies of etiopathogenesis and treatment.